Ambiguous association between NYHA class and CV outcomes in patients with HF
Associations Between New York Heart Association Classification, Objective Measures, and Long-term Prognosis in Mild Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial
Introduction and methods
The NYHA classification system places patients with HF in one of four categories according to their degree of symptoms and limitations during physical activity. However, this widely used NYHA classification system is subject to limitations. For instance, it poorly correlates with cardiopulmonary exercise tests, and therefore fails to discriminate subgroups of HF patients across the spectrum of functional impairment [1-3]. Substantial overlap in objective measures exists, in particular for those classified as NYHA I and II. Consequently, patients with mild HF may be misclassified, i.e., classified in NYHA class I instead of NYHA class II, and be ineligible for therapies. Furthermore, changes in physician-assigned NYHA class may have low prognostic value .
Aim of the study
The aim of this study was to assess: (1) within-patient variation in NYHA class over 12 months after randomization; (2) the association between NYHA class and an objective measure of HF severity, such as NT-proBNP; and (3) their association with long-term prognosis. For these analyses, data from the PARADIGM-HF trial were used.
The PARADIGM-HF trial was a multicenter, double-blind, randomized clinical trial in which 8399 patients with chronic HF, LVEF ≤40%, and elevated levels of BNP or NT-proBNP were randomly assigned to either sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily.
This secondary analysis compared data of 8326 patients classified as NYHA I to III at randomization Of these, 389 were classified as NYHA class I, 5919 were classified as NYHA class II, and 2018 were classified as NYHA class III.
Primary outcome was CV death or first HF hospitalization.
NYHA class variation in year 1
- Most patients remained functionally stable during the first year after randomization. At 4 months, 82% preserved their functional class; from 4 to 8 months, 85% of patients did; and from 8 to 12 months, 85%.
- In year 1, 58% of patients in NYHA class I changed functional class.
Association between objective measures and NYHA class
- For NT-proBNP, at an individual level, the estimated kernel density overlap was 93% between NYHA class I vs. class II, 79% between NYHA class I vs. class III, and 83% between NYHA class II vs. III.
- NT-proBNP levels were a poor predictor of NYHA classification: for NYHA class I vs. II, the AUC was 0.51 (95%CI: 0.48- 0.54); for NYHA I vs. III, 0.57 (95%CI: 0.54-0.60); and for NYHA II vs. III, 0.56 (95%CI: 0.54-0.57).
- For LVEF, the kernel density overlap was 74% between NYHA I vs. II, 67% between NYHA I vs. III, and 88% between NYHA II vs. III.
- Overlaps between NYHA classes were lower for KCCQ-CSS and varied from 25% between NYHA I vs. III to 53% between NYHA I vs II.
- Correlations between NYHA class and NT-proBNP levels (Spearman ρ=0.08) and between NYHA class and LVEF (ρ=0.07) were weak, and were low to intermediate between NYHA class and KCCQ-CSS (ρ=−0.40) (all P<0.001).
Prognostic value of NYHA class
- Those classified as having NYHA class III had a higher rate of cardiovascular events compared to those with NYHA class I (HR: 1.84; 95%CI: 1.44-2.37; P<0.001) or class II (HR: 1.49; 95%CI: 1.35-1.64; P<0.001). Patients in NYHA class I had a lower rate of events than those in NYHA class II (HR: 1.24; 95%CI: 0.97-1.58; P =0.09).
- After stratification by NT-proBNP levels (<1600 pg/mL or ≥1600 pg/mL),NYHA class I patients with higher NT-proBNP levels had a higher event rate than patients with lower NT-proBNP levels classified as NYHA I (HR: 3.43; 95%CI: 2.03-5.87; P<0.001), NYHA II (HR: 2.12, 95%CI: 1.58-2.86; P<0.001), or NYHA III (HR 1.37; 95%CI: 1.00-1.88; P=0.05).
Variation of NYHA class and outcomes
- In a model adjusted for baseline NYHA and changes in functional status to 4 months, improvement (HR 0.79, 95%CI: 0.68-0.93, P=0.004) and worsening of NYHA class (HR 1.90; 95%CI: 1.53-2.37, P<0.001) were significantly associated with events after 4 months.
- In a model adjusted for NYHA at 4 months and changes in functional status, improvement (HR 1.17, 95%CI:0.97-1.41, P=0.09) and worsening (HR 1.22, 95%CI: 0.98-1.51, P=0.08) of NYHA class were not associated with risk.
This study shows that the association between NYHA classification and cardiovascular outcomes among patients with HF is ambiguous. Higher NYHA classification is associated with worse prognosis. NYHA class I patients with high NT-proBNP levels manifested higher event rates than patients with lower NT-proBNP levels from any class. The authors concluded that NYHA classification as the main criterion to select treatment should be questioned as NYHA class alone fails to accurately differentiate mild forms of HF.